Fundamental Clinical Neuroscience ‐ 6
Demyelinating diseases
Multiple Sclerosis
Key features
Definition:
‐ autoimmune, chronic inflammatory, demyelinating disease of the CNS
‐ intermittent episodic neurologic impairments of varying severity caused by ‐ multiple demyelinating lesions, often of different ages
Key pathologic features: ‐ Perivenular inflammation with primary myelin loss and ‐ relative sparing of axons (early in disease)
Significant axonal destruction as disease progresses
Demyelination and axonal injury confined to CNS
Subtypes include relapsing‐remitting, primary progressive (secondary progressive, and progressive relapsing types)
Epidemiology
Prevalence 10 to 100 per 100,000 individuals depending on region
Affects all ages, most commonly found in individuals 18 to 50 years old
Overall female predominance (2 : 1 female‐to‐male ratio)
Incidence increases in northern latitudes
Risk factors: exposure to Epstein‐Barr virus, vitamin D deficiency, smoking
Presentation
Highly variable
Relapsing‐remitting type (85% of cases): sporadic attacks last 2 to 10 days followed by improvement over several months
Primary progressive type (15% of cases): clinical course is progressive without remissions or relapses
Secondary progressive type: conversion of relapsing/remitting to progressive disease
Optic neuritis may be first manifestation of disease
Prognosis, Treatment
5% of patients will have rapidly progressive deterioration
Average of 30 years from disease onset until death
Corticosteroids for acute relapses; plasmapheresis may help
Immunomodulatory medications: interferon beta‐1a and beta‐
1b, mitoxantrone, natalizumab
Imaging
MRI: ovoid T2‐hyperintense white matter lesions (“plaques”), particularly in periventricular regions; may have associated oedema in acute cases
T1‐hypointense lesions (“holes”) may represent chronic tissue axonal damage or more severe injury
Multiple
Sclerosis
Macroscopy
Coronal sections demonstrate irregularly shaped, glistening, grayish foci of demyelination (plaques) involving periventricular, subpial, and gray‐white matter junctions
Plaques can involve the cerebrum, cerebellum, brain stem, spinal cord, and optic nerve/chiasm; often involve gray + white matter
Atrophy of cerebral hemispheres, corpus callosum, optic nerve/chiasm, and hydrocephalus ex vacuo can be seen in long‐
standing disease
Peripheral nervous system not affected
Multiple Sclerosis
Multiple Sclerosis
Multiple Sclerosis
Multiple Sclerosis
Multiple Sclerosis
Multiple Sclerosis
Microscopy
Myelin loss with relative axonal sparing; activity categorized based on macrophage presence
Chronic inactive plaques (CIP): hypocellular neural tissue
demonstrating loss of oligodendrocytes with residual axonal processes
and variable presence of perivascular lymphocytes and plasma cells
Chronic active plaques (CAP): peripherally located macrophages surrounding the hypocellular neural tissue characterizing chronic inactive plaques
Special methods
Immunohistochemistry for neurofilament protein shows sparing of axons in demyelinated foci
Histochemical stain for Luxol fast blue (LFB): pallor of myelin staining;
periodic acid‐Schiff (PAS): myelin breakdown products within macrophages
Immunostains: CD3+ T cells, CD20+ B cells, and CD68+ macrophages Multiple Sclerosis ‐ CIP
Multiple Sclerosis ‐ CIP
Multiple Sclerosis ‐ CIP
Multiple Sclerosis – CIP with reactive
astrocytes
Multiple Sclerosis – CIP with cavitation
Multiple Sclerosis – CIP
Multiple Sclerosis ‐ CIP
Multiple Sclerosis – CIP & ‘shadow plaque’
Multiple Sclerosis – chronic active
plaque (CAP)
Multiple Sclerosis ‐ CAP
Multiple Sclerosis – CAP Multiple Sclerosis – CAP with macrophages
Multiple Sclerosis ‐ CAP
Multiple Sclerosis – acute
demyelinative lesion
Ti1 – Gadolinum contrast
Flair
Multiple Sclerosis –
acute demyelinative
lesion
Multiple Sclerosis – acute
demyelinative lesion
CD3
CD20
MS – Differential diagnosis
Glial neoplasm
Cerebral infarct
Nutritional/metabolic white matter disorders
Inherited leukodystrophies
Hypoxic‐ischaemic/toxic/infectious leukoencephalopathy
Multiple Sclerosis – Baló variant
Progressive (rarely remitting/relapsing)
Rings may be caused by hypoxia Hence, subsequent attacks form concentric rings
Multiple Sclerosis – Baló variant
Multiple Sclerosis – Baló variant
LFB/PAS
LFB/PAS
LFB/HE
Bielschowsky
Neuromyelitis optica (NMO)
A spectrum of demyelinating disorders that classically affect
the spinal cord (transverse myelitis) and optic nerve (optic
neuritis) and may affect other areas of cerebral white matter.
Classic NMO (Devic disease): monophasic myelitis and optic neuritis with absence of disease elsewhere in CNS Relapsing NMO: recurrent episodes of optic neuritis and myelitis; may have symptoms of brainstem dysfunction
NMO – Epidemiology
Predilection for East Asian and African populations
Affects all ages (median age 41 for relapsing, 29 for monophasic)
Female predominance (3 : 1 to 9 : 1)
aquaporin‐4 autoantibodies in 75% of cases
NMO occasionally associated with infections (mycobacterium, dengue fever, varicella zoster, cytomegalovirus), autoimmune
diseases (Sjögren's syndrome, lupus, myasthenia gravis)
Presentation, prognosis
Transverse myelitis: paraparesis, sensory loss, bladder or
bowel dysfunction
Optic neuritis: loss of visual fields and decreased visual acuity
by 5 years; 10% mortality
Neuromyelitis optica
(Devic)
Cavitating
lesions in
Optic chiasm
Neuromyelitis optica
(Devic)
Rarely: brainstem lesions
Neuromyelitis optica
Neurofilament